Fecal Transplant Experiments Show the Microbiome’s Role in the Aging Process

Longevity researchers have good reason to suspect a causal rather than bystander role for age-related microbiome changes. A unifying theme arising from some of the best-studied models of aging is the central role of the intestines as a critical determinant in lifespan. In C. elegans, the expression of a longevity gene in the animals’ nerves produced a modest (~10%) life extension and in their muscles had no effect on lifespan at all. Expressed in their intestines however it increased lifespan by 50 to 60 percent.

In fruit flies, age-related changes in their gut microbiomes precedes a loss of intestinal barrier function that ultimately leads to death. The lifespan of individual flies can be predicted by this gut leakiness. How do we know their microbiomes have anything to do with it? Because if you give 10 day old flies the equivalent of a fecal transplant from a 30 day old fly, their young gut starts to leak and they die sooner compared to getting microbiota from another 10 day old. We suspect the driver is the acquisition of bad bugs from the older flies rather than the loss of good bugs, since antibiotic treatment significantly increases their lifespan.

Invertebrates are one thing. What about in an animal with a backbone? African turquoise killifish are a popular aging model since they naturally only live a few months, allowing for rapid experimental turnarounds. What happens when you recolonize the guts of middle-aged fish with bacteria from younger fish? They live longer lives. They were also significantly more active later in life (in terms of spontaneous exploratory behavior). So, at least in the African turquoise killifish, age-related microbiome changes appear not-to-be-just a passive consequence of getting older, but an active driver of the aging process.

When they just gave antibiotics to the middle-aged fish to wipe out their gut flora entirely, they also lived longer, suggesting bad bugs were limiting their lifespan, but they didn’t live as long as the fish transplanted with the younger fish feces. So there appeared to be some salutary effect of the good bugs of youth. What happens when you do the reverse and give young fish the microbiome of an older fish. Presumably they’d live shorter lives, right? But no, nothing happens. That’s interesting. The researchers suggest that the lethal combination is therefore an age-ed immune system facing an age-ed microbiome. The young fish may be able handle the old microbiome because its youthful immune system is able to reshape it.

What about in mammals? The lifespan of microbe-free mice, those without a gut microbiome at all and raised under germ-free conditions like the “Bubble Boy,” is increased by up to 50 percent. They appear to be protected from inflamm-aging, the rise in systemic inflammation as we get older. Are gut bugs to blame for that inflammatory increase? Apparently so, since compared to feeding germ-free mice poop from young mice, old mouse poop causes a leaky gut to develop, bacteria toxins to spill into the bloodstream, and system-wide inflammation to develop.

Fecal transplant studies are how we can prove the role of the gut microbiome in disease processes. If individual A has disease X and you can reliably cause disease X in healthy individual B just by transferring fecal matter from the gut of A to B, then you can conclude that the microbiome plays a causal role in the disease. For ethical reasons, these kind of studies aren’t be performed in people. All we can do is try to transfer positive microbiome attributes. How, then, can we determine if a disease state is microbiome-related? The most common approach is to feed feces from affected patients to microbe-free mice and see how they do compared to microbe-free mice fed feces from healthy people as a control group.

There have been at least 38 such experiments published, and 36 (95 percent!) found that the pathology could be transferred through poop. This was the case even for conditions not thought to necessarily be gut related. For example, if you feed microbe-free mice from the diaper of a baby with a milk allergy, the mice end up with a milk allergy! So maybe our gut microbiome can help explain why the prevalence of food allergies has been rising so much in recent decades. Regardless, what about using this model to explore the role of our gut flora in aging?

Centenarian stool, has anti-aging effects, when fed to mice. Researchers forced mice to ingest fecal matter from an elderly individual (age 70), which was found to contain Bilophila wadsworthia, a pro-inflammatory bacteria enriched by a diet high in animal products, versus feces from a 101-year-old containing more fiber feeders. Mice transplanted with the centenarian microbiome ended up displaying a range of youthful physiological indicators, including less age pigment in their brains. This raises the possibility that we will one-day be using centenarian fecal matter to promote healthy aging. Why bathe in the blood of virgins when you can dine on the dung of the venerable?